This is an application for support for a SCOR in Osteoarthritis at Rush- Presbyterian-St. Luke's Medical Center in Chicago. It represents a continuation and an extension of the current SCOR grant with closely related projects within an integrated program entitled "Osteoarthritis: A Continuum (From Cartilage Metabolism to Early Detection and Treatment)". Investigators will study the components of cartilage especially the collagens and proteoglycans which together with the chondrocytes determine the simplest unit structure of cartilage. The investigators intend to study how these components interact to generate higher orders of aggregate organization forming a microenvironment for the cell. We intend to define the cellular heterogeneity of this stratified cartilage tissue and how the adjacent tissues which line the joint form a common functional organ. We plan to test the synergy and systemic influences of a single joint on multiple, distant diarthroidal joints. Finally, in the human knee we will study the effect of pain and analgesics on gait adaptations which ultimately protect or exacerbate the destruction of articular cartilage. Specifically, the proposal addresses structure and function of cartilage matrix resulting from the metabolism of dissimilar subpopulations of chondrocyte; the question of the formation and assembly as well as degradation of the extracellular cartilage matrix; metabolic modulation of normal chondrocytes in response to stimuli (e.g. IL-1 including signal transduction; osmotic changes and matrix injury); and metabolic differences and changes in cartilage from human joints which differ in occurrence of osteoarthritis (OA) (e.g. knee: high incidence vs. ankle: low incidence). As we gain knowledge on cartilage metabolism at the molecular level, studies directed towards questions of cartilage repair both in vivo and in vitro are proposed. Through our experience with current biochemical markers of cartilage metabolism (e.g., keratan sulfate), as well as recently identified novel marker-molecules of cartilage layers we will examine the effect of injury in one joint on other joints, and test our hypothesis of a systemic component to OA within an animal model and in patients. Additionally, we will undertake analyses of functional biomechanics (gait analyses) of patients treated by non-invasive methods (disease modifying agents) and compare gait before and after surgical intervention of knee OA. To address these issues funding for seven projects and three supportive core facilities is requested. Investigators are drawn from five academic departments: the Departments of Biochemistry; Orthopedic Surgery, (including the programs in biomechanics and biochemistry); Medicine (the Section of Rheumatology); Pathology; and Anatomy. The current well documented, substantial interactions and collaborations among the investigators make Rush an optimal site for the SCOR in OA.